Formulations of low dose diclofenac and beta-cyclodextrin

ABSTRACT

The present invention is directed to a pharmaceutical composition containing a unit dose of a diclofenac compound effective to induce analgesia; and a beta-cyclodextrin compound; wherein the dose of the diclofenac compound is less than 10 mg. The present invention is also directed to methods of treating a subject in need of analgesia with the pharmaceutical compositions of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 13/106,697, filed on May 12, 2011, which is acontinuation of U.S. patent application Ser. No. 11/689,931, filed onMar. 22, 2007, now U.S. Pat. No. 8,580,954, which claims priority under35 U.S.C. §119, based on U.S. Provisional Application No. 60/786,486,filed on Mar. 28, 2006, the disclosures of which are incorporated hereinby reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions andmethods of treating a subject in need of analgesia with pharmaceuticalcompositions which contain diclofenac and beta-cyclodextrin.Specifically, the compositions contain low doses of diclofenac, namelyless than 10 mg.

BACKGROUND OF THE INVENTION

Diclofenac is a well-known non-steroidal anti-inflammatory drug(“NSAID”) used in acute and chronic pain in both parenteral and oraldosage forms. Oral dosages range from 100-200 mg/day, while parenteraldosages range from 75-150 mg/day (1-2 mg/kg/day) by either infusion orintermittent (divided) doses. Toxicity of oral and parenteral forms arewell known, with gastro-intestinal, hemorrhagic, renal, hepatic,cardiovascular and allergic (anaphylactic and severe dermal allergy)adverse events being most significant.

Parenteral use of diclofenac has been limited due to limited solubility,such that parenteral preparations have had to include non-polar solventsin order to achieve concentrations (75 mg/3 ml) which would allowintra-muscular (IM) administration of the desired dose. This solubilityhas limited the parenteral use to IM use and/or slow intravenous (IV)administration of diluted (100-500 ml diluent) product.

U.S. Pat. No. 5,679,660 and co-pending application Ser. No. 10/999,155,filed Nov. 30, 2004, published as US 2005/0238674 A1 on Oct. 27, 2005,both of which are incorporated by reference, disclose novel formulationsof diclofenac with hydroxypropyl-beta-cyclodextrin, which allows a moreconcentrated preparation and thus rapid intravenous administration. Thedata show that the more concentrated the diclofenac/beta-cyclodextrinformulation, the faster onset of action over current products.

Other than ease of administration and more rapid onset of action,consequent on the improvements in the pharmaceutical formulation, noother advantages were observed. The present invention arises, in part,from the surprising discovery that formulating a non-steroidalanti-inflammatory drug with beta-cyclodextrin not only improvessolubility and stability of the drug, it also increases efficacy.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisinga unit dose of a diclofenac compound effective to induce analgesia; anda beta-cyclodextrin compound, in which the dose of the diclofenaccompound is less than 10 mg. This dose is less than any effective dosepreviously reported or even suggested for a formulation of a diclofenacand a beta-cyclodextrin compound. The diclofenac compound can be adiclofenac salt, e.g., diclofenac sodium, as exemplified infra. Thebeta-cyclodextrin compound can be 2-hydroxypropyl-beta-cyclodextrin, asexemplified infra.

The pharmaceutical composition may further comprise a stabilizer, suchas monothioglycerol.

In specific embodiments, the pharmaceutical composition provides a doseof diclofenac of about 9.4 mg, less than about 5 mg, and even about 3.75mg.

The invention further provides a method for treating a mammal in need ofanalgesia by administering a pharmaceutical composition of theinvention, as set forth above. In a specific embodiment, the mammal is ahuman. In particular, the pharmaceutical composition can be administeredintravenously.

The advantageous methods of the invention pertain to other formulationsas well. Thus, the invention provides a method for treating a mammal inneed of analgesia by administering a pharmaceutical compositioncomprising a dosage of a diclofenac compound effective to induceanalgesia; and a beta-cyclodextrin compound, in which the dosage of thediclofenac compound is less than about 1.3 mg/kg per day. In particularembodiments, the dosage of diclofenac is less than 0.65 mg/kg per day,less than 0.33 mg/kg per day, or less than 0.165 mg/kg per day.

In another embodiment of the methods of treatment, the inventionprovides a method for treating a mammal in need of analgesia byadministering a pharmaceutical composition comprising a dosage of adiclofenac compound effective to induce analgesia; and abeta-cyclodextrin compound, wherein the dosage of the diclofenaccompound is less than a minimum approved dose for a particular route ofadministration. The dose of the diclofenac compound can have the sameefficacy of pain relief as the minimum approved dose, or it can havefrom about 70% to about 100% or from about 40% to about 70% of theefficacy of pain relief as the minimum approved dose. In addition, thedose of the diclofenac compound can have the same duration of painrelief as the minimum approved dose, or it can have from abouttwo-thirds to the same duration of pain relief, or from about one-thirdto about two-thirds of the duration of pain relief, as the minimumapproved dose.

DESCRIPTION OF THE FIGURES

FIG. 1 contains a graphical representation of the 100 mm visual analogpain relief (mm) afforded to patients over time (hours) based on theformulation strengths administered. The tested formulations includeplacebo, 3.75 mg Dyloject, 9.4 mg Dyloject, 18.75 mg Dyloject; 37.5 mgDyloject, 75 mg Dyloject, and 30 mg Ketorolac.

FIG. 2 illustrates the dose-response curve for peak analgesia observed(mm VAS) over mg of formulation. Both diclofenac and ketorolacformulations were tested.

FIG. 3 illustrates the dose-duration relationship examined using themedian time to re-medication (hours) in the single dose phase. Twoformulations of diclofenac were studied.

FIG. 4 illustrates the percentage of patients with NSAID Adverse Eventsby dose of diclofenac (mg).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides formulations of a diclofenac compoundwith a beta-cyclodextrin compound. These formulations unexpectedlyprovide for significant efficacy and duration of pain relief at a lowerdose than the current recommended doses of the diclofenac. Moreparticularly, at a reduced dose and dosage, the formulation provides thesame level of efficacy and the same duration of analgesia as at theminimum approved dose and dosage.

The invention is based, in part, on the results of a comparison of theefficacy of diclofenac solubilized with hydroxypropyl-beta-cyclodextrinto ketorolac and placebo for the treatment of moderate-to-severepost-surgical pain. The efficacy of diclofenac solubilized withhydroxypropyl-beta-cyclodextrin at several dose levels suggests a fasteronset of action. Most notably, diclofenac formulated withhydroxypropyl-beta-cyclodextrin provides single-dose efficacy at about50%, about 25%, about 12.5% and about 5% of the current recommendeddoses of diclofenac. This, in combination with the known humanpharmacokinetic results for the formulation, supports reduced totaldaily doses of this NSAID with anticipated lower risk of toxicity byreducing the extent and duration of drug exposure. This is a novelfinding and of clinical importance.

The minimum effective dose of diclofenac solubilized withhydroxypropyl-beta-cyclodextrin tested was 3.75 mg, demonstrating thatdiclofenac, if solubilized with hydroxypropyl-beta-cyclodextrin, may beadministered at doses lower than those previously considered necessaryfor postoperative analgesia.

The term “diclofenac compound” refers to diclofenac or apharmaceutically acceptable diclofenac salt. A pharmaceuticallyacceptable salt of diclofenac, can be an alkali metal salt, for examplethe sodium or the potassium salt, or the salt formed with an amine,e.g., a mono-, di- or tri-C₁-C₄ alkylamine, for example diethyl- ortriethyl-amine, hydroxy-C₂-C₄ alkylamine, for example ethanolamine, orhydroxy-C₂-C₄ alkyl-C₁-C₄ alkylamine, for example dimethylethanolamine,or a quaternary ammonium salt, for example the tetramethylammonium saltor the choline salt of diclofenac (see, e.g., U.S. Pat. No. 5,389,681).Preferably the diclofenac salt is diclofenac sodium.

Suitable formulations of the present invention for parenteraladministration include cyclodextrin inclusion complexes. One or moremodified or unmodified cyclodextrins can be employed to stabilize andincrease the water solubility and efficacy of compounds of the presentinvention. Useful cyclodextrins for this purpose includebeta-cyclodextrins.

The term “beta-cyclodextrin” as used herein refers to cyclicalpha-1,4-linked oligosaccharides of a D-glucopyranose containing arelatively hydrophobic central cavity and hydrophilic outer surface.Particular efficacy has been observed in the present invention utilizinghydroxypropyl-beta-cyclodextrin, however, other substituted andunsubstituted beta-cyclodextrins can also be used in the practice of theinvention. Additional examples of cyclodextrins that may be utilized aredisclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, 5,024,998, 6,407,079,6,828,299, 6,869,939 and Jambhekar et al., 2004 Int. J Pharm. 2004,270(1-2) 149-66. The formulations may be prepared as described in U.S.Pat. Nos. 5,679,660 and 5,674,854.

The “pharmaceutical compositions” for use in accordance with the presentinvention can be formulated in any conventional manner using one or morepharmaceutically acceptable carriers or excipients. A “pharmaceuticallyacceptable” carrier or excipient, as used herein, the term“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in mammals, and moreparticularly in humans.

Pharmaceutical compositions include solid dosage forms, e.g., forperioral, transnasal (powder), or rectal (suppository) administration;and liquid dosage forms, e.g., for parenteral administration(injection), transnasal (spray), or perioral administration. In aspecific embodiment, the pharmaceutical compositions of the presentinvention are liquid compositions formulated for intravenous orintramuscular administration, and particularly intravenousadministration.

As used herein, the term “stabilizer” refers to a compound optionallyused in the pharmaceutical compositions of the present invention inorder to avoid the need for sulphite salts and increase storage life.Optimal stabilizers include antioxidants, specifically monothioglyceroland those described in U.S. Patent Publication 2005/0238674.

The term “dosage” is intended to encompass a formulation expressed interms of mg/kg/day. The dosage is the amount of an ingredientadministered in accordance with a particular dosage regimen. A “dose” isan amount of an agent administered to a subject in a unit volume ormass, e.g., an absolute unit dose expressed in mg of the agent. The dosedepends on the concentration of the agent in the formulation, e.g., inmoles per liter (M), mass per volume (m/v), or mass per mass (m/m). Thetwo terms are closely related, as a particular dosage results from theregimen of administration of a dose or doses of the formulation. Theparticular meaning in any case will be apparent from context.

The term “mammal” is intended to include, any warm-blooded vertebratehaving the skin more or less covered with hair. Most preferably, themammal is a human subject, but the mammal can also be a non-humananimal. Thus, the invention is useful in veterinary medicine as well,e.g., for treating pain in a domestic pet, such as a canine or feline, afarm animal, a work animal, or an animal in a circus or zoologicalgarden. The invention has particular value in treating pain in a horse,particularly in sport, such as thoroughbred and other race horses, rodeohorses, circus horses, and dressage horses. A particular advantage ofthe invention is that, by increasing the efficacy of a dosage ofdiclofenac, it is possible to administer a therapeutic dosage that isbelow a maximum allowed dose permitted by the particular regulatoryauthorities of the sport.

The term “minimum approved dose” refers to the minimum dosage that hasreceived full regulatory approval by the appropriate United States orforeign regulatory authority as safe and effective for human orveterinary use.

The term “therapeutically effective” as applied to dose or amount refersto that quantity of a compound or pharmaceutical composition that issufficient to result in a desired activity upon administration to amammal in need thereof As used herein with respect to the pharmaceuticalcompositions comprising an antifungal, the term “therapeuticallyeffective amount/dose” refers to the amount/dose of a compound orpharmaceutical composition that is sufficient to produce an effectiveresponse upon administration to a mammal.

The term “amount” as used herein refers to quantity or to concentrationas appropriate to the context. In the present invention, the effectiveamount of a compound refers to an amount sufficient to treat apatient/subject in need of analgesia. The effective amount of a drugthat constitutes a therapeutically effective amount varies according tofactors such as the potency of the particular drug, the route ofadministration of the formulation, and the mechanical system used toadminister the formulation. A therapeutically effective amount of aparticular drug can be selected by those of ordinary skill in the artwith due consideration of such factors.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 3 or more than 3 standard deviations,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, preferably up to 10%, more preferably up to 5%, and morepreferably still up to 1% of a given value. Alternatively, particularlywith respect to biological systems or processes, the term can meanwithin an order of magnitude, preferably within 5-fold, and morepreferably within 2-fold, of a value.

As used herein, the term “treat” is used herein to mean to relieve oralleviate at least one symptom of a disease in a subject. Within themeaning of the present invention, the term “treat” also denotes toarrest, delay the onset (i.e., the period prior to clinicalmanifestation of a disease) and/or reduce the risk of developing orworsening a disease.

Methods of Treatment

As noted above, the novel dosage formulations of the invention aresuitable for administering diclofenac to treat pain, i.e., foranalgesia. Various embodiments of the invention provide foradministration of unit doses to achieve a total dosage for the desiredeffect. The examples demonstrate efficacy of a 3.75 mg dose ofdiclofenac, which is about 5% of the minimum approved dose (and about 5%or about 2.5% of the approved daily dosage). However, this dose providesabout 40% of the pain relief and one-third of the duration as theminimum approved dose. Better results can be achieved by selecting adosage regimen with this dose of diclofenac, e.g., increasing thefrequency of administration, to achieve a level and duration of painrelief acceptable for the patient. Higher dose formulations likewisecould provide such relief Such higher dose formulations are neverthelesslower than any approved formulation, and the dosage regimen results inadministration of less diclofenac than the current approved minimumdosage regimen.

A significant advantage of the invention results from the ability toachieve efficacy with lower doses and overall daily dosing ofdiclofenac. Consequently, it is possible to reduce the dosage, and thusreduce toxicity.

In specific embodiments, the unit dose (i.e., the amount of active drugadministered at one time to a patient) is no more than about 75%, nomore than about 50%, no more than about 25%, no more than about 12.5%,and no more than about 5%, of the approved minimum dose. Doses that areabout or greater than about 50% of the approved minimum dose can showthe same level and duration of pain relieve as the minimum effectivedose. Furthermore, by increasing the frequency of administration of alower dose formulation, the patient can achieve the same levels ofefficacy and duration of pain relief as with the approved doses, withdecreased toxicity.

In another embodiment, then, the invention provides for titrating thedose reduction of diclofenac and beta-cyclodextrin by decreasing theunit dose to achieve an analgesic effect that is sufficient, even at areduced level, for the patient's needs, which can be met by increasingthe dosing frequency to achieve an effective daily dosage that is stilllower than the minimum approved dose. The term “effect” means that thereis a statistically significant difference in a response in patientstaking the formulation containing the diclofenac relative to patientstaking a placebo.

The formulations of the invention can be administered via any route,including parenteral, perioral, transnasal, and rectal. Particularparenteral routes of administration include intravenous andintramuscular injection.

The formulations of the invention are suitable for treating pain byadministration either or both prophylactically and after onset of thepain. Thus, as used herein, the term “treat” (in any of its grammaticalforms) means to reduce pain through administration of a formulation ofthe invention prior to or after the onset of pain, or both. Inparticular, the formulations are suitable in the treatment of acutepainful conditions in humans and animals such as headache, includingmigraine, trauma, dysmenorrhoea, renal or biliary colic, post-operativepain, gout, arthritis, cancer related pain, musculoskeletal pain, lowerback pain, fibromyalgia, and pain of infectious origin. Indeed, the lowdosage of diclofenac will have little or no anti-inflammatory activity,so in the treatment of pain of infectious origin it will have littleeffect on any immune response to the infectious organism while achievinganalgesia. In a specific embodiment, exemplified below, the formulationis effective to treat post-surgical dental pain resulting from surgicalextraction of one or more third molars. In addition, although notintending to be bound by any particular mechanism of action, theformulation of the invention may be used prophylactically to prevent theformation of prostaglandins during and after surgery, with subsequentreduction in immediate post-operative pain. Further, the formulation ofthe invention may be used to modulate nuclear transcription factors,such as NF-κB, or to modulate ion channel activity, for example asdescribed in Ocana, Maria et al., Potassium Channels and Pain: PresentRealities and Future Opportunities, 500 Eur. J. Pharm. 203 (2004).

EXAMPLES

The present invention will be better understood by reference to thefollowing Examples, which are provided as exemplary of the invention,and not by way of limitation.

Example 1 Analysis of Pain Relief Afforded to Patients Based onAdministered Dose

A 336-patient, seven treatment arm, randomized, double-blind,single-dose, and placebo- and comparator-controlled, parallel-groupstudy was conducted. Patients were randomly assigned to receive a singledose of either diclofenac sodium solubilized withhydroxypropyl-beta-cyclodextrin (hereinafter “DIC”), ketorolactromethamine, or placebo.

Bolus IV injectable 2 ml solutions were prepared by solubilizingdiclofenac sodium with hydroxypropyl-beta-cyclodextrin. The formulationstrengths were as follows:

Formulation: Diclofenac sodium solubilized withhydroxypropyl-β-cyclodextrin

Strengths: 75 mg, 37.5 mg, 18.75 mg, 9.4 mg and 3.75 mg

Dosage: Bolus IV injection (no less than 15 sec)

Batch Number: 063004 (PPS04010)

Manufacturer: Manufactured for Javelin by Precision Pharma

Storage Conditions: Room temperature

Active control/comparator:

Formulation: Ketorolac Tromethamine

Strength: 30 mg

Dosage: Bolus IV injection (no less than 15 sec)

Batch Number: 21-430-DK

Manufacturer: Abbott Labs

Storage Conditions: Room temperature

Pain was assessed by each patient at Baseline (0 hour: Visual AnalogScale (VAS) and categorical pain intensity only), at 5, 15, 30 and 45minutes, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours afteradministration of study medication and immediately prior to the firstdose of rescue medication. At each post-dose time period, levels of painintensity (categorical and VAS) and pain relief (categorical and VAS)was assessed by each patient. Patients were also provided with 2stopwatches to measure perceptible and meaningful pain relief.

The presence of a dose-response was tested with a step-down testingprocedure. Total pain relief (TOTPAR), peak pain relief, pain intensitydifference (SPID), summed peak reduction in pain intensity difference(SPRID), and patient global evaluation was analyzed with analysis ofvariance (ANOVA) with treatment, center, and baseline categorical painintensity as factors. The possibility of interactions was investigated.Comparisons of the DIC groups with the placebo and Ketorolac groups wereperformed with Dunnett's test. The presence of a linear dose responsefor the ordered DIC dose levels was tested with orthogonal contrasts forTOTPAR, SPID and SPRID. Tests of individual DIC dose levels versusplacebo for TOTPAR, SPID, and SPRID were conducted with the Tukey,Ciminera, and Heyse step-down testing procedure. The mean, standarddeviation, and sample size were presented for each treatment group.Significant p-values (those less than or equal to 0.05) were presentedfor each step of the procedure. Non-significant p-values wererepresented with three dashes. Time to onset of perceptible relief andtime to onset of meaningful relief was analyzed with survival analysistechniques. These variables were summarized with number of observations,mean, standard deviation, median, and range. Log-rank tests were used tocompare treatments with respect to survival distributions. The mediantime to event for each treatment group was estimated with theKaplan-Meier product limit estimator. A 95% confidence interval for eachestimated median time to event was calculated.

The results of the study were strongly positive, novel and could nothave been anticipated from prior experience with diclofenac. The doseshad been chosen based on the currently recommended minimally effectivedoses of 1 mg/kg (50 mg immediate-release or 100 mg sustained-releaseorally or 75 mg intramuscularly or intravenously). Based on these dosesthe test conditions were a full dose (75 mg), half dose (37.5) mg, apossibly effective dose (18.75 mg) and two placebo doses (9.75 & 3.4mg). The findings were as follows:

TABLE 1 TOTPAR (Sum of Pain Relief VAS 0-100 mm ratings 0-6 hours)Treatment Group Result % Maximum Effect Placebo 62.8 (SEM 9) 17% DIC3.75 mg 134.1 (SEM 8)  38% DIC 9.4 mg 237.6 (SEM 15) 68% DIC 18.75 mg284.4 (SEM 21) 82% DIC 37.5 mg 348.2 (SEM 30) 100% DIC 75 mg 346.3 (SEM27) 100% ketorolac 400.3 (SEM 36) 100%

See FIG. 1 for the corresponding graphical representation of the painrelief afforded to patients based on the formulation strengthsadministered.

Example 2 Analysis of Efficacy & Duration of Pain Relief at Lower Dosesof Diclofenac

To explore this further, the dose-duration relationship in the samestudy was examined using the median time to remedication in thesingle-dose phase. Utilizing the results of study in Example 1, theefficacy and duration of pain relief were thoroughly analyzed. Thelowest IV dose of DIC (3.75 mg) had 38% of the effect of the maximaldose, and the next lowest dose (9.4 mg) had 68% of the maximal possibleeffect, despite being 5% and 12% respectively of the current recommendedminimally effective dose (1 mg/kg). FIG. 2 contains a graphicalillustration of the dose-response for peak analgesia observed in thestudy.

FIG. 3 depicts the dose-duration relationship examined using the mediantime to remedication in the single dose phase. The peak analgesicresponse was about 80% pain relief, with a 50% response at a dose of 4-8milligrams of Diclofenac in relation to dental pain. Similar peakanalgesic response was seen for 30 milligrams of ketorolac. Given theshape of the dose response curve, it is clear that lower doses of theDIC formulation achieved the same results as the current establisheddose of diclofenac of 75 milligrams.

The findings show a 6 hour duration of effect for all doses above about20 milligrams (18 milligrams).

For most drugs the findings of significant activity at doses far belowthe recommended doses would be of little significance due to largetherapeutic indices (wide ranges between the effective and toxic doses).The opposite is true for parenteral NSAIDs; it has been well establishedin the prior art that increasing the dose of these drugs rapidlydiminishes their utility due to increasing risk of toxicity.

Thus the finding that with the new formulation of diclofenac that 5%-12%of the usual dose can provide 38-68% of the desired therapeutic effectis remarkable and unanticipated. This leads to the possibility that thehigh early blood levels possible with the new formulation allow lowertotal daily doses resulting in less risk of toxicity.

This finding demonstrates efficacy with a lower daily dose (25-75mg/day) than current dosing of diclofenac (75-200 mg/day), andanticipates better dosing paradigms (less than Q 12 hours) offering theexpectation of lesser toxicity. Proof of lesser toxicity from availabledata from this study is suggestive, based on the known relationship ofdose and toxicity.

The novel diclofenac formulation allowed by hydroxypropyl-β-cyclodextrinhas been shown to provide proof of single-dose efficacy at 50%, 25%,12.5% and 5% of the current recommended doses of diclofenac. This incombination with the known human pharmacokinetic results for theformulation supports reduced total daily doses of this NSAID withanticipated lower risk of toxicity by reducing the extent and durationof drug exposure.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

Patents, patent applications publications product descriptions, andprotocols are cited throughout this application the disclosures of whichare incorporated herein by reference in their entireties for allpurposes.

What is claimed is:
 1. A pharmaceutical composition comprising fromabout 18.75 mg to about 37.5 mg of a diclofenac compound solubilizedwith a beta-cyclodextrin compound.
 2. The pharmaceutical composition ofclaim 1, wherein the diclofenac compound is diclofenac sodium.
 3. Thepharmaceutical composition of claim 1, wherein the beta-cyclodextrincompound is hydroxypropyl beta-cyclodextrin.
 4. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition isformulated for a parenteral route of administration.
 5. Thepharmaceutical composition of claim 1, wherein the dose of thediclofenac compound is about 18.75 mg.
 6. The pharmaceutical compositionof claim 1, wherein the dose diclofenac compound is about 37.5 mg. 7.The pharmaceutical composition of claim 1, further comprising astabilizer.
 8. The pharmaceutical composition of claim 4, wherein theparenteral route of administration is intravenous or intramuscular. 9.The pharmaceutical composition of claim 1, wherein the composition isstable at room temperature.